Therapeutic agent delivery device with controlled therapeutic agent release rates

ABSTRACT

The present invention relates to implantable medical devices for the localized delivery of therapeutic agents, such as drugs, to a patient. More particularly, the invention relates to a device having a gradient of water soluble therapeutic agents within a therapeutic agent layer and a mixing layer that allows for controlled release of the therapeutic agents.

FIELD OF THE INVENTION

The invention relates to a therapeutic agent delivery device whichcomprises a gradient of therapeutic agent within mixing layers whichprovides for the controlled release of water soluble therapeutic agents.

DESCRIPTION OF THE RELATED ART

Implantable medical devices are often used for delivery of a beneficialagent, such as a drug, to an organ or tissue in the body at a controlleddelivery rate over an extended period of time. These devices may deliveragents to a wide variety of bodily systems to provide a wide variety oftreatments.

One of the many implantable medical devices which have been used forlocal delivery of beneficial agents is the coronary stent. Coronarystents are typically introduced percutaneously, and transportedtransluminally until positioned at a desired location. These devices arethen expanded either mechanically, such as by the expansion of a mandrelor balloon positioned inside the device, or expand themselves byreleasing stored energy upon actuation within the body. Once expandedwithin the lumen, these devices, called stents, become encapsulatedwithin the body tissue and remain a permanent implant.

Known stent designs include monofilament wire coil stents (U.S. Pat. No.4,969,458); welded metal cages (U.S. Pat. Nos. 4,733,665 and 4,776,337);and, most prominently, thin-walled metal cylinders with axial slotsformed around the circumference (U.S. Pat. Nos. 4,733,665; 4,739,762;and 4,776,337). Known construction materials for use in stents includepolymers, organic fabrics and biocompatible metals, such as stainlesssteel, gold, silver, tantalum, titanium, and shape memory alloys, suchas Nitinol.

Of the many problems that may be addressed through stent-based localdelivery of beneficial agents, one of the most important is restenosis.Restenosis is a major complication that can arise following vascularinterventions such as angioplasty and the implantation of stents. Simplydefined, restenosis is a wound healing process that reduces the vessellumen diameter by extracellular matrix deposition, neointimalhyperplasia, and vascular smooth muscle cell proliferation, and whichmay ultimately result in renarrowing or even reocclusion of the lumen.Despite the introduction of improved surgical techniques, devices, andpharmaceutical agents, the overall restenosis rate is still reported inthe range of 25% to 50% within six to twelve months after an angioplastyprocedure. To treat this condition, additional revascularizationprocedures are frequently required, thereby increasing trauma and riskto the patient.

One of the techniques under development to address the problem ofrestenosis is the use of surface coatings of various beneficial agentson stents. U.S. Pat. No. 5,716,981, for example, discloses a stent thatis surface-coated with a composition comprising a polymer carrier andpaclitaxel (a well-known compound that is commonly used in the treatmentof cancerous tumors). The patent offers detailed descriptions of methodsfor coating stent surfaces, such as spraying and dipping, as well as thedesired character of the coating itself: it should “coat the stentsmoothly and evenly” and “provide a uniform, predictable, prolongedrelease of the anti-angiogenic factor.” Surface coatings, however, canprovide little actual control over the release kinetics of beneficialagents. These coatings are necessarily very thin, typically 5 to 8microns deep. The surface area of the stent, by comparison is verylarge, so that the entire volume of the beneficial agent has a veryshort diffusion path to discharge into the surrounding tissue.

Increasing the thickness of the surface coating has the beneficialeffects of improving drug release kinetics including the ability tocontrol drug release and to allow increased drug loading. However, theincreased coating thickness results in increased overall thickness ofthe stent wall. This is undesirable for a number of reasons, includingincreased trauma to the vessel wall during implantation, reduced flowcross-section of the lumen after implantation, and increasedvulnerability of the coating to mechanical failure or damage duringexpansion and implantation. Coating thickness is one of several factorsthat affect the release kinetics of the beneficial agent, andlimitations on thickness thereby limit the range of release rates,duration of drug delivery, and the like that can be achieved.

In addition to sub-optimal release profiles, there are further problemswith surface coated stents. The fixed matrix polymer carriers frequentlyused in the device coatings typically retain approximately 30% of thebeneficial agent in the coating indefinitely. Since these beneficialagents are frequently highly cytotoxic, sub-acute and chronic problemssuch as chronic inflammation, late thrombosis, and late or incompletehealing of the vessel wall may occur. Additionally, the carrier polymersthemselves are often highly inflammatory to the tissue of the vesselwall. On the other hand, use of biodegradable polymer carriers on stentsurfaces can result in the creation of “virtual spaces” or voids betweenthe stent and tissue of the vessel wall after the polymer carrier hasdegraded, which permits differential motion between the stent andadjacent tissue. Resulting problems include micro-abrasion andinflammation, stent drift, and failure to re-endothelialize the vesselwall.

Another significant problem is that expansion of the stent may stressthe overlying polymeric coating causing the coating to plasticallydeform or even to rupture, which may therefore effect drug releasekinetics or have other untoward effects. Further, expansion of such acoated stent in an atherosclerotic blood vessel will placecircumferential shear forces on the polymeric coating, which may causethe coating to separate from the underlying stent surface. Suchseparation may again have untoward effects including embolization ofcoating fragments causing vascular obstruction.

In addition, it is not currently possible to deliver some drugs with asurface coating for a variety of reasons. In some cases, the drugs aresensitive to water, other compounds, or conditions in the body whichdegrade the drugs. For example, some drugs lose substantially all theiractivity when exposed to water for a period of time. When the desiredtreatment time is substantially longer than the half life of the drug inwater the drug cannot be delivered by know coatings. Other drugs, suchas protein or peptide based therapeutic agents, lose activity whenexposed to enzymes, pH changes, or other environmental conditions. Andfinally drugs that are highly-soluble in water tend to be released fromthe coatings at an undesirably high rate and do not remain localized fora therapeutically useful amount of time. These types of drugs which aresensitive to compounds or conditions in the body often cannot bedelivered using surface coatings.

Accordingly, it would be desirable to provide a beneficial agentdelivery device for delivery of agents, such as drugs, to a patientwhile protecting the agent from compounds or conditions in the bodywhich would degrade the agent.

SUMMARY OF THE INVENTION

The present invention relates to medical device for the controlleddelivery of therapeutic agents where the release of the therapeuticagent is mediated by a mixing layer.

In one of its device aspects the present invention provides for animplantable medical device comprising an implantable device body havinga plurality of holes; a therapeutic agent provided in a firsttherapeutic agent layer and contained within the plurality of holes inthe device body; and at least one mixing layer provided adjacent thefirst therapeutic agent layer in the plurality of holes; wherein thetherapeutic agent layer and the at least one mixing layer togethercontain a concentration gradient of said therapeutic agent and allow forthe controlled release of the therapeutic agent contained within thetherapeutic agent layer and the at least one mixing layer.

In another of its device aspects the present invention provides for animplantable medical device comprising an implantable device body havinga plurality of holes; a therapeutic agent within the plurality of holesin the device body provided in a therapeutic agent layer; and a mixinglayer provided in the plurality of holes; wherein the therapeutic agentlayer and the mixing layer contain a concentration gradient of saidtherapeutic agent created by delivering a mixing layer material withoutthe therapeutic agent and liquefying a portion of the therapeutic agentlayer with the mixing layer material, whereby the mixing layer has alesser amount of therapeutic agent contained therein than thetherapeutic agent layer.

The mixing layers are preferably a pharmaceutically acceptablebioresorbable matrix, more preferably pharmaceutically acceptablepolymers. Even more preferably the mixing layers are selected from thegroup consisting of polylactic acid, polyglycolic acid,polylactic-co-glycolic acid, polylactic acid-co-caprolactone,polyethylene glycol, polyethylene oxide, poly lactic acid-btock-polyethylene glycol, poly glycolic acid-block-poly ethylene glycol, polylactide-co-glycolide-block-poly ethylene glycol, poly ethyleneglycol-block-lipid, polyvinyl pyrrolidone, poly vinyl alcohol, aglycosaminoglycan, polyorthoesters, polysaccharides, polysaccharidederivatives, polyhyaluronic acid, polyalginic acid, chitin, chitosan,chitosan derivatives, cellulose, hydroxyethylcellulose,hydroxypropylcellulose, carboxymethylcellulose, polypeptides,polylysine, polyglutamic acid, albumin, polyanhydrides, polyhydroxyalkonoates, polyhydroxy valerate, polyhydroxy butyrate, proteins,polyphosphate esters, lipids, and mixtures thereof.

The therapeutic agent layer preferably comprises the therapeutic agentand a water soluble binding agent. The water soluble binding agent ispreferably selected from poly ethylene glycol, poly ethylene oxide, polyvinylpyrrolidone, poly vinyl alcohol, a glycosaminoglycan,polysaccharides, polysaccharide derivatives, poly hyaluronic acid, polyalginic acid, chitin, chitosan, chitosan derivatives, cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose, poly peptides, poly lysine, poly glutamic acid, and proteins,such as albumin.

The liquefied therapeutic agent layer comprises from about 20% to about95% therapeutic agent and from about 5% to about 70% pharmaceuticallyacceptable polymer preferably from about 50% to about 95% therapeuticagent and from about 5% to about 50% pharmaceutically acceptablepolymer, more preferably from about 50% to about 60% therapeutic agentand from about 40% to about 50% pharmaceutically acceptable polymer.

The therapeutic agent is preferably antithrombotic agents, aantineoplastic agent, a neoplastic agent, an antiproliferative agent, anantisense compound, an immunosuppresant, an angiogenic agent, anangiogenic factor, an antiangiogenic agent, or an anti-inflammatoryagent, or combinations thereof. More preferably the therapeutic agent isof 2-chlorodeoxyadenosine, bivalirudin, Resten NG, or anoliogonucleotide, or mixtures thereof.

The therapeutic agent maybe homogeneously or heterogeneously dispersedin the therapeutic agent layer and/or the mixing layer(s). Thetherapeutic agent may be homogeneously or heterogeneously disposed in alayer as a solid particle dispersion, encapsulated agent dispersion, anemulsion, a suspension, a liposome, niosome, or a microparticle, whereinsaid niosome, liposome or microparticle comprise a homogeneous orheterogeneous mixture of the therapeutic agent. When a therapeutic agentis homogeneously disposed in a therapeutic agent layer, it may be asolid-solution or a multi-phase mixture.

Optionally the liquefied bioresorbable polymer loaded into the holesdoes not contain the therapeutic agent.

The implantable medical device is useful in the treatment of restenosisand inflammation and is preferably a stent.

The bioresorbable polymers, binding agents of the individual layers maybe the same or different. In one embodiment, the polymers used in thetherapeutic agent layer is different than the polymer used in the mixinglayer. The polymers and binging agents of the individual layers maybeliquified by dissolution of the materials in a solvent or by maintainingthe materials at a temperature that is higher than their melting points,or glass transition temperatures.

The implantable medical device may optionally further comprise a barrierlayer, wherein the barrier layer is located adjacent the therapeuticagent layer. The barrier layer is formed by loading into the pluralityof holes an amount of a liquified biocompatible polymer, which amount issufficient to form a barrier layer, wherein the barrier layer is locatedadjacent the therapeutic agent layer.

In one of its method aspects the present invention provides for anmethod for preparing an implantable medical device as described hereinabove, which method comprises:

a) providing an implantable medical device with a plurality of holes;

b) loading into the plurality of holes an amount of a liquifiedtherapeutic agent, which amount is sufficient to form a therapeuticagent layer;

c) allowing said liquified therapeutic agent layer to at least partiallysolidify;

d) loading into the plurality of holes an amount of a liquifiedbioresorbable polymer which amount is sufficient to liquify a portion ofthe therapeutic agent layer, thereby allowing a portion of thetherapeutic agent layer to be disposed within a mixing layer;

e) allowing said liquified bioresorbable polymer and said portion of thetherapeutic agent layer to solidify;

wherein an amount of therapeutic agent contained within the mixing layerupon solidification is smaller than an amount of therapeutic agentcontained in the therapeutic agent layer and further wherein steps d ande may optionally be repeated to form multiple mixing layers.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

The invention will now be described in greater detail with reference tothe preferred embodiments illustrated in the accompanying drawings, inwhich like elements bear like reference numerals, and wherein:

FIG. 1 is a perspective view of a therapeutic agent delivery device inthe form of an expandable stent.

FIG. 2 is a cross sectional view of a portion of a therapeutic agentdelivery device having a beneficial agent contained in an opening inlayers.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a delivery device for delivery of watersoluble therapeutic agents to a patient. More particularly, theinvention relates to a medical device having therapeutic agentsprotected from premature release into a patient by one or more mixinglayers. Details for the device design, therapeutic agents, therapeuticagent layers, and mixing layers may also be found in U.S. patentapplication Ser. No. 10/253,020, filed on Sep. 23, 2002, incorporatedherein by reference in its entirety. First, the following terms, as usedherein, shall have the following meanings:

The term “beneficial agent” as used herein is intended to have itsbroadest possible interpretation and is used to include any therapeuticagent or drug, as well as inactive agents such as barrier layers,carrier layers, therapeutic layers or mixing layers.

The terms “drug” and “therapeutic agent” are used interchangeably torefer to any therapeutically active substance that is delivered to abodily conduit of a living being to produce a desired, usuallybeneficial, effect. The present invention is particularly well suitedfor the delivery of antineoplastic, angiogenic factors,immuno-suppressants, and antiproliferatives (anti-restenosis agents)such as paclitaxel, Rapamycin or 2-chlorodeoxyadenosine, for example,and antithrombins such as heparin, for example.

The therapeutic agents used in the present invention include classicallow molecular weight therapeutic agents commonly referred to as drugsincluding all classes of action as exemplified by, but not limited to:antineoplastic, immuno-suppressants, antiproliferatives, antithrombins,antiplatelet, antilipid, anti-inflammatory, angiogenic, anti-angiogenic,vitamins, ACE inhibitors, vasoactive substances, antimitotics,metello-proteinase inhibitors, NO donors, estradiols, anti-sclerosingagents, alone or in combination. Therapeutic agent also includes highermolecular weight substances with drug like effects on target tissuesometimes called biologic agents including but not limited to: peptides,lipids, protein drugs, protein conjugates drugs, enzymes,oligonucleotides, ribozymes, genetic material, prions, virus, bacteria,and eucaryotic cells such as endothelial cells, monocyte/macrophages orvascular smooth muscle cells to name but a few examples. The therapeuticagent may also be a pro-drug, which metabolizes into the desired drugwhen administered to a host. In addition, the therapeutic agents may bepre-formulated as a microcapsules, microspheres, microbubbles,liposomes, niosomes, emulsions, dispersions or the like before it isincorporated into the therapeutic layer. The therapeutic agent may alsobe radioactive isotopes or agents activated by some other form of energysuch as light or ultrasonic energy, or by other circulating moleculesthat can be systemically administered.

A water soluble drug is one that has a solubility of greater than 1.0mg/mL in water at body temperature.

The term “matrix” or “biocompatible matrix” are used interchangeably torefer to a medium or material that, upon implantation in a subject, doesnot elicit a detrimental response sufficient to result in the rejectionof the matrix. The matrix typically does not provide any therapeuticresponses itself, though the matrix may contain or surround atherapeutic agent, and/or modulate the release of the therapeutic agentinto the body. A matrix is also a medium that may simply providesupport, structural integrity or structural barriers. The matrix may bepolymeric, non-polymeric, hydrophobic, hydrophilic, lipophilic,amphiphilic, and the like.

The term “bioresorbable” refers to a matrix, as defined herein, that canbe broken down by either chemical or physical process, upon interactionwith a physiological environment. The matrix can erode or dissolve. Abioresorbable matrix serves a temporary function in the body, such asdrug delivery, and is then degraded or broken into components that aremetabolizable or excretable, over a period of time from minutes toyears, preferably less than one year, while maintaining any requisitestructural integrity in that same time period.

The term “pharmaceutically acceptable” refers to a matrix or anadditive, as defined herein, that is not toxic to the host or patient.When in reference to a matrix, it provides the appropriate storageand/or delivery of therapeutic, activating or deactivating agents, asdefined herein, and does not interfere with the effectiveness or thebiological activity of the agent.

The term “mixing layer” refers to a matrix layer which is adjacent atherapeutic agent layer. Before the mixing layer is introduced to thedevice, the mixing layer preferably contains no therapeutic agent, or itcontains a therapeutic agent which is different from the therapeuticagent of the therapeutic agent layer. The mixing layer is introduced ina liquified state and may mix with the therapeutic agent layer causingthe mixing layer to incorporate a portion of the adjacent therapeuticagent layer once the layer has at least partially solidified. The mixinglayer may also serve to control the rate at which a drug is releasedinto the reaction environment. The release rate can be controlled by therate of erosion or dissolution of the mixing layer or by the rate ofdiffusion of the therapeutic agent from within the mixing andtherapeutic agent layers. The mixing layer is preferably bioresorbable.

The term “erosion” refers to the process by which the components of amedium or matrix are bioresorbed and/or degraded and/or broken down byeither chemical or physical processes. For example in reference topolymers, erosion can occur by cleavage or hydrolysis of the polymerchains, such that the molecular weight of the polymer is lowered. Thepolymer of lower molecular weight will have greater solubility in waterand is therefore dissolved away. In another example, erosion occurs byphysically breaking apart upon interaction with a physiologicalenvironment.

The term “erosion rate” is a measure of the amount of time it takes forthe erosion process to occur and is usually report in unit area per unittime.

The term “degrade” or “deactivate” refers to any process that causes anactive component, such as a therapeutic agent, to become unable, or lessable, to perform the action which it was intended to perform whenincorporated in the device.

The term “polymer” refers to molecules formed from the chemical union oftwo or more repeating units, called monomers. Accordingly, includedwithin the term “polymer” may be, for example, dimers, trimers andoligomers. The polymer may be synthetic, naturally-occurring orsemisynthetic. In preferred form, the term “polymer” refers to moleculeswhich typically have a M_(w) greater than about 3000 and preferablygreater than about 10,000 and a M_(w) that is less than about 10million, preferably less than about a million and more preferably lessthan about 200,000. Examples of polymers include but are not limited to,poly-α-hydroxy acid esters such as, polylactic acid, polyglycolic acid,polylactic-co-glycolic acid, polylactic acid-co-caprolactone;polyethylene glycol and polyethylene oxide, polyvinyl pyrrolidone,polyorthoesters; polysaccharides and polysaccharide derivatives such aspolyhyaluronic acid, polyalginic acid, chitin, chitosan, chitosanderivatives, cellulose, hydroxyethylcellulose, hydroxypropylcellulose,carboxymethylcellulose; polypeptides, and proteins such as polylysine,polyglutamic acid, albumin; polyanhydrides; polyhydroxy alkonoates suchas polyhydroxy valerate, polyhydroxy butyrate, and the like.

The term “lipid”, as used herein, refers to a matrix that comprisespreferably non-polymeric small organic, synthetic ornaturally-occurring, compounds which are generally amphipathic andbiocompatible. The lipids typically comprise a hydrophilic component anda hydrophobic component. Exemplary lipids include, for example, fattyacids, fatty acid esters, neutral fats, phospholipids, glycolipids,aliphatic alcohols, waxes, terpenes, steroids and surfactants. Termlipid is also meant to include derivatives of lipids. More specificallythe term lipids includes but is not limited to phosphatidylcholine,phosphatidylethanolamine, phosphatidylserine, sphingomyelin as well assynthetic phospholipids such as dimyristoyl phosphatidylcholine,dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine,distearoyl phosphatidylglycerol, dipalmitoyl phosphatidyl-glycerol,dimyristoyl phosphatidylserine, distearoyl phosphatidylserine anddipalmitoyl phosphatidylserine.

The term “additives” refers to pharmaceutically acceptable compounds,materials, and compositions that may be included in a matrix along witha therapeutic agent. An additive may be encapsulated in or on or arounda matrix. It may be homogeneously or heterogeneously disposed, asdefined herein, in the matrix. Some examples of additives arepharmaceutically acceptable excipients, adjuvants, carriers,antioxidants, preservatives, buffers, antacids, and the like, such asthose disclosed in Remington: The Science and Practice of Pharmacy,Gennaro, ed., Mack Publishing Co., Easton, Pa., 19th ed., 1995.

The term “holes” refers to holes of any shape and includes boththrough-openings and recesses.

The term “reaction environment” or “environment” refers to the areabetween a tissue surface abutting the device and the first intact layerof beneficial agent within a hole in the medical device.

The term “liquified” is used herein to define a component which is putin a liquid state either by heating the component to a temperaturehigher than its melting point, or glass transition temperature, or bydissolving the component in a solvent. The typical liquified materialsof the present invention will have a viscosity of less than about 13,000centipoise, and preferably less about 10,000 centipoise.

The term “homogeneously disposed” or “homogeneously dispersed” refers toa mixture in which each of the components are uniformly dispersed withinthe matrix.

The term “heterogeneously disposed” or “heterogeneously dispersed”refers to a mixture in which the components are not mixed uniformly intoa matrix.

The term “solid solution” refers to a homogeneously dispersed mixture oftwo or more substances. A component that is mixed uniformly in a matrixin such a manner that the component is macroscopically indistinguishablefrom the matrix itself. An example of a solid solution is a metal alloy,such as brass.

The term “multi-phase mixture” refers to a mixture of two or moresubstances in which at least one component is macroscopicallydistinguishable from the matrix itself. An example of a multi-phasemixture is a macro emulsion.

Implantable Medical Devices with Holes

FIG. 1 illustrates a medical device 10 according to the presentinvention in the form of a stent design with large, non-deforming struts12 and links 14, which can contain holes 20 without compromising themechanical properties of the struts or links, or the device as a whole.The non-deforming struts 12 and links 14 may be achieved by the use ofductile hinges 16 which are described in detail in U.S. Pat. No.6,241,762 which is incorporated hereby by reference in its entirety. Theholes 20 serve as large, protected reservoirs for delivering variousbeneficial agents to the device implantation site.

The relatively large, protected openings 20, as described above, makethe expandable medical device of the present invention particularlysuitable for delivering larger molecules or genetic or cellular agents,such as, for example, protein drugs, enzymes, antibodies, antisenseoligonucleotides, ribozymes, gene/vector constructs, and cells(including but not limited to cultures of a patient's own endothelialcells). Many of these types of agents are biodegradable or fragile, havea very short or no shelf life, must be prepared at the time of use, orcannot be pre-loaded into delivery devices such as stents during themanufacture thereof for some other reason. The large holes 20 in theexpandable device of the present invention form protected areas orreceptors to facilitate the loading of such an agent either at the timeof use or prior to use, and to protect the agent from abrasion andextrusion during delivery and implantation.

The volume of beneficial agent that can be delivered using holes 20 isabout 3 to 10 times greater than the volume of a 5 micron coatingcovering a stent with the same stent/vessel wall coverage ratio. Thismuch larger beneficial agent capacity provides several advantages. Thelarger capacity can be used to deliver multi-drug combinations, eachwith independent release profiles, for improved efficacy. Also, largercapacity can be used to provide larger quantities of less aggressivedrugs and to achieve clinical efficacy without the undesirableside-effects of more potent drugs, such as retarded healing of theendothelial layer.

Holes also decrease the surface area of the beneficial agent bearingcompounds to which the vessel wall surface is exposed. For typicaldevices with beneficial agent openings, this exposure decreases by afactors ranging from about 6:1 to 8:1, by comparison with surface coatedstents. This dramatically reduces the exposure of vessel wall tissue topolymer carriers and other agents that can cause inflammation, whilesimultaneously increasing the quantity of beneficial agent delivered,and improving control of release kinetics.

FIG. 2 shows a cross section of a medical device 10 in which one or morebeneficial agents have been loaded into the opening 20 in discretelayers 30. Examples of some methods of creating such layers andarrangements of layers are described in U.S. patent application Ser. No.09/948,989, filed on Sep. 7, 2001, which is incorporated herein byreference in its entirety.

According to one example, the total depth of the opening 20 is about 125to about 140 microns, and the typical layer thickness would be about 2to about 50 microns, preferably about 12 microns. Each typical layer isthus individually about twice as thick as the typical coating applied tosurface-coated stents. There would be at least two and preferably aboutten to twelve such layers in a typical opening, with a total beneficialagent thickness about 4 to 28 times greater than a typical surfacecoating. According to one preferred embodiment of the present invention,the openings have an area of at least 5×10⁻⁶ square inches, andpreferably at least 7×10⁻⁶ square inches.

Since each layer is created independently, individual chemicalcompositions and pharmacokinetic properties can be imparted to eachlayer. Numerous useful arrangements of such layers can be formed, someof which will be described below. Each of the layers may include one ormore agents in the same or different proportions from layer to layer.The layers may be solid, porous, or filled with other drugs orexcipients.

FIG. 2 shows an arrangement of layers provided in a through opening 20which include a barrier layer 30, one or more therapeutic agent layers40, and a plurality of mixing layers 50. The barrier layer 30substantially prevents delivery of the therapeutic agent in thetherapeutic agent layers and the mixing layers from being delivered to aside of the device 10 adjacent the barrier layer. The therapeutic agentlayer 40 and the mixing layers 50 are loaded sequentially into themedical device opening 20, such that a concentration gradient oftherapeutic agent is present with a highest concentration of therapeuticagent at the interior layers closer to the barrier layer and a lowestconcentration of therapeutic agent at the exterior mixing layers. Thecombination of therapeutic agent layer and mixing agent layers allows awater soluble therapeutic agent to be delivered over an extended timeperiod of time. The time period for delivery can be modulated fromminutes, to hours, to days. Preferably the time period for delivery isgreater than 1 day, more preferably greater than 3 days.

In one embodiment the layers are loaded into the medical device by firstloading the therapeutic agent layer, 40, into the holes of the medicaldevice in a liquefied state. The therapeutic agent layer is then allowedto solidify. A first mixing layer, 50, is then loaded into the holeswithin the medical device in a liquefied state. When the liquid mixinglayer, 50, comes into contact with the therapeutic agent layer, 40, aportion of the therapeutic agent layer is liquefied allowing aco-mingling of some of the components of each of the two layers. Whenthe mixing layer solidifies, there is therapeutic agent within themixing layer.

Optionally, a second mixing layer is then loaded into the holes withinthe medical device in a liquefied state. When the second liquid mixinglayer comes into contact with the first mixing layer, a portion of thefirst mixing layer is liquefied allowing a co-mingling of some of thecomponents of each of the two layers. When the mixing layer solidifies,there is an amount of therapeutic agent within the second mixing layerthat is less than the amount of therapeutic agent in the first mixinglayer. Subsequent additions of mixing layers results in the formation ofmultiple mixing layers with decreasing amounts of therapeutic agent. Thegradient of therapeutic agent incorporated in a mixing layers adjacentthe therapeutic agent layer is especially advantageous for the deliveryof water soluble drugs such as a 2-chlorodeoxyadenosine.

An example of a binding agent is Poly vinylpyrrolidone. The polymers ofthe therapeutic agent layer may be the same as or different from thepolymer of the mixing layers. The polymer can be liquefied bymaintaining the material at a temperature that is greater than itsmelting point, or glass transition temperature, or by dissolution in asolvent.

Some examples of hydrophobic, bioresorbable matrix materials for themixing layer are lipids, fatty acid esters, such as glycerides. Theerosion rate is controlled by varying the hydrophilic-lipophilic balance(HLB). The polymers of the individual mixing layers may be the same ordifferent. These polymers can be liquefied by maintaining the materialat a temperature that is greater than its melting point, or glasstransition temperature, or by dissolution in a solvent.

Bioerosion of the mixing layers may induce the release of thetherapeutic agent from either the mixing layer or the therapeutic agentlayer. However, in some embodiments, the mixing layer remainsessentially intact, and the therapeutic agent is released into thereaction environment by diffusing from the therapeutic agent layer andthrough the mixing layers.

Therapeutic Layer Formulations

The therapeutic agent layers of the present invention may consist of thetherapeutic agent alone or a therapeutic agent in combination with abioresorbable matrix. The matrix of the therapeutic agent layers can bemade from pharmaceutically acceptable polymers, such as those typicallyused in medical devices. This polymer may also be referred to as abinding agent. Typically, when a lesser amount of matrix material isused relative to the amount of drug, for example 5–50% polymer to 95–50%drug, the material is called a binding agent.

Polymers useful in the therapeutic agent layer as either a matrixmaterial or a binding agent are well known and include but are notlimited to poly-α-hydroxy acid esters such as, polylactic acid,polyglycolic acid, polylactic-co-glycolic acid, polylacticacid-co-caprolactone; polyethylene glycol and polyethylene oxide; polyvinyl alcohol, polyvinyl pyrrolidone; polyorthoesters; polysaccharidesand polysaccharide derivatives such as polyhyaluronic acid, aglycosaminoglycan, polyalginic acid, chitin, chitosan, chitosanderivatives, cellulose, hydroxyethylcellulose, hydroxypropylcellulose,carboxymethylcellulose; polypeptides, and proteins such as polylysine,polyglutamic acid, albumin; polyanhydrides; polyhydroxy alkonoates suchas polyhydroxy valerate, polyhydroxy butyrate, and the like, andcopolymers thereof. Particularly useful polymers include poly ethyleneglycol, poly ethylene oxide, poly vinylpyrrolidone, poly vinyl alcohol,polysaccharides and their derivatives, poly hyaluronic acid, polyalginic acid, chitin, chitosan, chitosan derivatives, cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose, poly peptides, poly lysine, poly glutamic acid, and proteins.These polymers and copolymers can be prepared by methods well known inthe art (see, for example, Rempp and Merril: Polymer Synthesis, 1998,John Wiley and Sons) in or can be used as purchased from Alkermes, inCambridge, Mass. or Birmingham Polymer Inc., in Birmingham, Ala.

The preferred polymer for use in the therapeutic layer of the presentinvention is poly vinylpyrrolidone (PVP). The rate at which the polymerresorbs is determined by the selection of the subsequently loaded mixinglayers.

Therapeutic Agent Formulations

Some drugs that are useful in the present invention are low molecularweight synthetic oligonucleotides and polypeptides, such as2-chlorodeoxyadenosine, restinase, or restin NG.

Typical formulations for therapeutic agents incorporated in thesemedical devices are well known to those skilled in the art and includebut are not limited to solid particle dispersions, encapsulated agentdispersions, and emulsions, suspensions, liposomes or microparticles,wherein said liposome or microparticle comprise a homogeneous orheterogeneous mixture of the therapeutic agent.

The amount of the drug that is present in the device, and that isrequired to achieve a therapeutic effect, depends on many factors, suchas the minimum necessary dosage of the particular drug, the condition tobe treated, the chosen location of the inserted device, the actualcompound administered, the age, weight, and response of the individualpatient, the severity of the patient's symptoms, and the like.

The appropriate dosage level of the therapeutic agent, for moretraditional routes of administration, are known to one skilled in theart. These conventional dosage levels correspond to the upper range ofdosage levels for compositions, including a physiologically activesubstance and traditional penetration enhancer. However, because thedelivery of the active substance occurs at the site where the drug isrequired, dosage levels significantly lower than a conventional dosagelevel may be used with success. Ultimately, the percentage oftherapeutic agent in the composition is determined by the requiredeffective dosage, the therapeutic activity of the particularformulation, and the desired release profile. In general, the activesubstance will be present in the composition in an amount from about0.0001% to about 99%, more preferably about 0.01% to about 80% by weightof the total composition depending upon the particular substanceemployed. However, generally the amount will range from about 0.05% toabout 75% by weight of the total composition.

Mixing Layer Formulations

The mixing layers of the present invention are comprised of abioresorbable matrix and optionally contain additional additives,therapeutic agents, activating agents, deactivating agents, and the likeas described in U.S. patent application Ser. No 10/253,020. In additionto the polymer materials described above, the mixing layer may also becomprised of pharmaceutically acceptable lipids or lipid derivatives,which are well known in the art and include but are not limited to fattyacids, fatty acid esters, lysolipids, phosphocholines, (Avanti PolarLipids, Alabaster, Ala.), including 1-alkyl-2-acetoyl-sn-glycero3-phosphocholines, and 1-alkyl-2-hydroxy-sn-glycero 3-phosphocholines;phosphatidylcholine with both saturated and unsaturated lipids,including dioleoylphosphatidylcholine; dimyristoyl-phosphatidylcholine;dipentadecanoylphosphatidylcholine; dilauroylphosphatidyl-choline;dipalmitoylphosphatidylcholine (DPPC); distearoylphosphatidylcholine(DSPC); and diarachidonyiphosphatidylcholine (DAPC);phosphatidyl-ethanolamines, such as dioleoylphosphatidylethanolamine,dipahnitoyl-phosphatidylethanolamine (DPPE) anddistearoylphosphatidylefhanolamine (DSPE); phosphatidylserine;phosphatidylglycerols, including distearoylphosphatidylglycerol (DSPG);phosphatidylinositol; sphingolipids such as sphingomyelin; glucolipids;sulfatides; glycosphingolipids; phosphatidic acids, such asdipahmitoylphosphatidic acid (DPPA) and distearoylphosphatidic acid(DSPA); palmitic acid; stearic acid; arachidonic acid; oleic acid;lipids bearing polymers, such as chitin, hyaluronic acid,polyvinylpyrrolidone or polyethylene glycol (PEG), also referred toherein as “pegylated lipids”, with preferred lipids bearing polymersincluding DPPE-PEG (DPPE-PEG), which refers to the lipid DPPE having aPEG polymer attached thereto, including, for example, DPPE-PEG5000,which refers to DPPE having attached thereto a PEG polymer having a meanaverage molecular weight of about 5000; lipids bearing sulfonated mono-,di-, oligo- or polysaccharides; cholesterol, cholesterol sulfate andcholesterol hemisuccinate; tocopherol hemisuccinate; lipids with etherand ester-linked fatty acids; polymerized lipids (a wide variety ofwhich are well known in the art); diacetyl phosphate; dicetyl phosphate;stearylamine; cardiolipin; phospholipids with short chain fatty acids ofabout 6 to about 8 carbons in length; synthetic phospholipids withasymmetric acyl chains, such as, for example, one acyl chain of about 6carbons and another acyl chain of about 12 carbons; ceramides; non-ionicliposomes including niosomes such as polyoxyethylene fatty acid esters,polyoxyethylene fatty alcohols, polyoxyethylene fatty alcohol ethers,polyoxyethylated sorbitan fatty acid esters, glycerol polyethyleneglycol oxystearate, glycerol polyethylene glycol ricinoleate,ethoxylated soybean sterols, ethoxylated castor oil,polyoxyethylene-polyoxypropylene polymers, and polyoxyethylene fattyacid stearates; sterol aliphatic acid esters including cholesterolsulfate, cholesterol butyrate, cholesterol iso-butyrate, cholesterolpalmitate, cholesterol stearate, lanosterol acetate, ergosterolpalmitate, and phytosterol n-butyrate; sterol esters of sugar acidsincluding cholesterol glucuronide, lanosterol glucuronide,7-dehydrocholesterol glucuronide, ergosterol glucuronide, cholesterolgluconate, lanosterol gluconate, and ergosterol gluconate; esters ofsugar acids and alcohols including lauryl glucuronide, stearoylglucuronide, myristoyl glucuronide, lauryl gluconate, myristoylgluconate, and stearoyl gluconate; esters of sugars and aliphatic acidsincluding sucrose diacetate hexaisobutyrate (SAIB), sucrose laurate,fructose laurate, sucrose palritate, sucrose stearate, glucuronic acid,gluconic acid and polyuronic acid; saponins including sarsasapogenin,smilagenin, hederagenin, oleanolic acid, and digitoxigenin; glyceroldilaurate, glycerol trilaurate, glycerol monolaurate, glyceroldipalmitate, glycerol and glycerol esters including glyceroltripalmitate, glycerol monopalmitate, glycerol distearate, glyceroltristearate, glycerol monostearate, glycerol monomyristate, glyceroldimyristate, glycerol trimyristate; long chain alcohols includingn-decyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, andn-octadecyl alcohol; 1,2-dioleoyl-sn-glycerol; 1,2-dipalmitoyl-sn-3-succinylglycerol; 1,3-dipalmitoyl-2-succinylglycerol;1-hexadecyl-2-palmitoylglycerophosphoethanolamine andpalmitoylhomocysteine, and/or combinations thereof.

If desired, a cationic lipid may be used, such as, for example,N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA),1,2-dioleoyloxy-3-(trimethylammonio)propane (DOTAP); and1,2-dioleoyl-3-(4′-trimethylammonio)butanoyl-sn-glycerol (DOTB). If acationic lipid is employed in the lipid compositions, the molar ratio ofcationic lipid to non-cationic lipid may be, for example, from about1:1000 to about 1:100. Preferably, the molar ratio of cationic lipid tonon-cationic lipid may be from about 1:2 to about 1:10, with a ratio offrom about 1:1 to about 1:2.5 being preferred. Even more preferably, themolar ratio of cationic lipid to non-cationic lipid may be about 1:1.

These lipid materials are well known in the art and can be used aspurchased from Avanti, Burnaby, B.C. Canada.

The preferred lipids for use in the present invention arephosphatidyl-choline, phosphatidylethanolamine, phosphatidylserine,sphingomyelin as well as synthetic phospholipids such as dimyristoylphosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoylphosphatidylcholine, distearoyl phosphatidyl-glycerol, dipalmitoylphosphatidylglycerol, dimyristoyl phosphatidylserine, distearoylphosphatidylserine and dipalmitoyl phosphatidylserine.

The rate at which the bioresorbable matrix resorbs is determined by thechoice of lipid, the molecular weight, and the ratio of the chosenmaterials.

The mixing layer can resorb by either chemical mechanisms such aschemical interactions, dissolution in water, hydrolysis, or reactionwith enzymes, or by physical erosion mechanisms.

Composite Matrix of Therapeutic Agent and Mixing Layers

Because of the methods used to make the implantable devices of thepresent invention, the therapeutic agent that is first incorporated inthe therapeutic agent layer is ultimately found throughout thetherapeutic agent layer and the mixing layers. Each layer is introducedinto the holes of the device while in a liquified state and then isallowed to solidify. A layer previously solidified within the wells ispartially liquefied again when a new liquified layer is introduced ontop of the existing solid layer. This allows for the materials of thesetwo layers to mix. The concentration of a therapeutic agent in a laterapplied layer is going to be smaller than the concentration oftherapeutic agent in the previously formed layers. This layer methodallows for a concentration gradient of therapeutic agent to be formed inthe layers within the medical device.

The mixing layer and the therapeutic agent layer, into which thetherapeutic agent is homogeneously or heterogeneously dispersed, mayeach be a homogeneous or heterogeneous mixture. For example, if thepolymers of the mixing layer and the polymers of the therapeutic agentlayer are mutually miscible, then the material contained within theholes of the implantable medical device will be a solid solution, or aone phase mixture, comprising each of these polymers. Examples ofpolymer systems that can form a one phase homogeneous mixture includebut are not limited to 1) polyvinyl pyrrolidone and poly vinyl alcohol,2) polyvinyl pyrrolidone and polyethylene glycol, 3) polyvinylpyrrolidone and polyalginate, and 4) polyvinyl pyrrolidone andcarboxymethylcellulose.

If the polymers comprising the mixing layer and therapeutic agent layerare only slightly miscible or are immiscible, then the materialcontained within the holes of the implantable medical device will be atwo phase (or phase separated) mixture comprising each of thesepolymers. The two phase mixture may be

i) phase domains of the mixing layer polymer dispersed in a continuousphase of the therapeutic agent layer polymer;

ii) phase domains of the therapeutic agent layer polymer dispersed in acontinuous phase of the mixing layer polymer; or

iii) two co-continuous phases each of the mixing layer polymer and thetherapeutic agent layer polymer.

The type of two-phase mixture is determined by judicious choice ofpolymer for each layer, and the percentage of each polymer thatdissolves in the solvent used to introduce the mixing layer(s). Examplesof polymer systems that can form a multi-phase homogeneous mixtureinclude but are not limited to 1) 50% by volume of polylactide and 50%by volume of poly vinylpyrrolidone 2) Poly(lactide-co-glycolide) andpolyethylene oxide, and 3) poly DL-lactide and polyethylene oxide.

Additionally, two phase mixtures can be prepared such that one phase isa homogeneous mixture of a first weight ratio of mixing layer polymerand therapeutic agent layer polymer and a second phase is a is ahomogeneous mixture of a second weight ratio of the same mixing layerpolymer and therapeutic agent layer polymer. Generally, to achieve phaseseparation and a resulting two phase mixture, one phase will consistlargely of mixing layer polymer and a second phase will consist largelyof therapeutic agent layer polymer.

The therapeutic agent maybe homogeneously or heterogeneously disposedwithin the homogeneous or heterogeneous matrix formed by the polymers ofthe mixing layer and the therapeutic agent layer. For example, if thetherapeutic agent is fully soluble in each of the mixing layer andtherapeutic agent layer polymers, then the distribution of thetherapeutic agent will be controlled by the relative solubility of theagent in each polymer and the relative miscibility of the polymers ineach other as well as their respective volume proportions. If thedesired amount of therapeutic agent exceeds the solubility in either orboth of the mixing layer or the therapeutic agent layer, then thetherapeutic agent can theoretically be found in four separate phaseswithin the final composite matrix.

1) homogeneously dissolved in the mixing layer polymer;

2) dispersed as a second phase within the mixing layer polymer;

3) homogeneously dissolved in the therapeutic agent layer polymer whichis itself in a continuous or non-continuous phase with respect to thetherapeutic agent layer; or

4) dispersed as a second phase within the therapeutic agent layerpolymer.

The distribution of the therapeutic agent, and thus the kinetic releaseprofile, may be controlled by the selection of the molecular weight ofthe polymer, the solubility of the polymer and the volume percentage ofeach of the polymers used within the mixing and the therapeutic agentlayers.

Any of the specific polymers or chemicals listed as a useful matrixmaterial for the mixing layer may also be used in the therapeutic agentlayer as a binder and vise-versa. Generally, the material chosen as abinding agent in therapeutic agent layer has different physicalproperties than the material used as the matrix in the mixing layers.This may be accomplished by using two different chemicals or polymers.Alternatively, the same type of polymer maybe used as long as thephysical properties, such as solubility, or hydrophobicity,hydrophilicity or melting point or glass transition temperature can bealtered by changing the polymers molecular weight or by addingadditional components or additives, such as co-polymers, elasticizers,plasticizers and the like.

The therapeutic agent, which can be heterogeneously or homogeneouslydispersed in the therapeutic agent layer and/or the mixing layer, can bea drug, or a drug formulated into a microcapsule, niosome, liposome,microbubble, microsphere, or the like. In addition, the mixing layer maycontain more than one therapeutic agent. For example, a water sensitivedrugs, such as a limus, or any other drug that must be administeredthrough intravenous, intramuscular, or subcutaneously, could beincorporated in a hydrophobic matrix such as SAIB, or fatty acid ester.

Bioresorbable polymers may also be used to form barrier layers thatresorb at a rate that can be predetermined base on the composition andthat contain no therapeutic agent.

In one embodiment, the mixing layers, 50, of the present invention areessentially hydrophobic and are bioresorbed at a rate that can beselected based on the polymers that are chosen in the formulation. Thetherapeutic agent layer, 40, is comprised of about 50% to about 60% of atherapeutic agent and about 40% to about 50% of a pharmaceuticallyacceptable bioresorbable polymer that acts primarily as a binding agent.

Uses for Implantable Medical Devices

Although the present invention has been describe with reference to amedical device in the form of a stent, the medical devices of thepresent invention can also be medical devices of other shapes useful forsite-specific and time-release delivery of drugs to the body and otherorgans and tissues. The drugs may be delivered to the vasculatureincluding the coronary and peripheral vessels for a variety oftherapies, and to other lumens in the body including the esophagus,urethera, and the bile duct. The drugs may increase lumen diameter,create occlusions, or deliver the drug for other reasons.

Medical devices and stents, as described herein, are useful for theprevention of amelioration of restenosis, particularly afterpercutaneous transluminal coronary angioplasty and intraluminal stentplacement. In addition to the timed or sustained release ofanti-restenosis agents, other agents such as anti-inflammatory agentsmay be incorporated in to the multi-layers incorporated in the pluralityof holes within the device. This allows for site-specific treatment orprevention any complications routinely associated with stent placementthat are known to occur at very specific times after the placementoccurs.

The methods for loading beneficial agents into openings in an expandablemedical device may include known techniques such as dipping and coatingand also known piezoelectric micro-jetting techniques. Micro-injectiondevices may be used to deliver precise amounts of one or more liquidbeneficial agents including mixing layers, therapeutic agent layers, andany other layers to precise locations on the expandable medical devicein a known manner. The beneficial agents may also be loaded by manualinjection devices.

EXAMPLES

In the examples below, the following abbreviations have the followingmeanings. If an abbreviation is not defined, it has its generallyaccepted meaning.

mL = milliliters M = Molar wt. = weight vol. = volume μL = microlitersμm = micrometers nm = nanometers DMSO = Dimethyl sulfoxide NMP =N-methylpyrrolidone DMAC = Dimethyl acetamide

Example 1 Formulation Comprising a Gradient of a Therapeutic Agentwithin the Mixing Layers

A first mixture of poly(lactide-co-glycolide) (PLGA) (BirminghamPolymers, Inc), lactide:glycolide::85:15, (M_(v)>100,000 Daltons) 7% wt.and a suitable organic solvent, such as DMSO, NMP, or DMAC 93% wt. isprepared. The mixture is loaded dropwise into holes in the stent, thenthe solvent is evaporated to begin formation of the barrier layer. Asecond barrier layer is laid over the first by the same method offilling polymer solution into the hole followed by solvent evaporation.The process is continued until five individual layers have been laiddown to form the barrier layer.

A second mixture of 2-chlorodeoxyadenosine, 50% solids basis, and polyvinylpyrrolidone (PVP), 50% solids basis, in a suitable organic solvent,such as DMSO, is introduced into holes in the stent over the barrierlayer. The solvent is evaporated to form a drug filled therapeutic agentlayer. The filling and evaporation procedure is repeated until the holeis filled to about 50% of its total volume with drug in therapeuticagent layer layered on top of the barrier layer.

Three layers of a third solution, of poly(lactide-co-glycolide) (PLGA),lactide:glycolide::50:50, (M_(v)≅80,000 Daltons) 8% wt. and a suitableorganic solvent, such as DMSO, are then laid down over the therapeuticagent layer to form three mixing layers. When each of the mixing layersis loaded into the stent, a portion of the layer beneath is incorporatedin the new layer. In this way multiple mixing layers are formedcontaining a concentration gradient of therapeutic agent.

Following implantation of the filled stent in vivo, the2-chlorodeoxyadenosine contained within the stent is delivered slowlyover a time period of about 1 to about 8 days. The barrier layerprevents the therapeutic agent from being delivered out the barrierlayer side of holes in the stent.

Example 2 Measurement of Drug Release Rates from a Medical Device withMultiple Therapeutic Agent Layers

A solution of phosphate buffered saline (PBS) is prepared by dissolvingfive “Phosphate Buffered Saline Tablets” (Sigma-Aldrich Co., catalog#P-4417) in 1000 mL deionized water to provide a solution with a pH of7.4, 0.01 M in phosphate buffer, 0.0027 M in potassium chloride and0.137 M in sodium chloride. This PBS solution is used as a ReleaseSolution.

The elution rate of drug from the multilayered stent of Example 1 isdetermined in a standard sink condition experiment.

A first 10 mL screw capped vial is charged with release solution, 3 mL,then placed in a shaking water bath held at 37° C. until temperature hasequilibrated. The above stent containing a concentration gradient ofdrug in the mixing layers is placed into the release solution, shakingat 60 cycles per minute commenced, and the stent is held immersed in therelease solution for a period of time. The stent is then placed in asecond screw capped vial is charged with release solution, 3 mL, at 37°C., and held for a period of time. The first release solution is calledsample #1. From time to time, the stent is removed from release solutionin one vial and placed into fresh solution in the next vial to generatea series of samples containing varying amounts of drug eluted from thestent.

The amount of drug in a given release solution sample is determined byHigh Pressure Liquid Chromatography (HPLC). The following conditions areused:

Analysis Column: Sym. C₁₈ (5 μm, 3.9×150 mm, Waters Corp., MA)

Mobile phase: Water/Acetonitrile :: 55% vol./45% vol.

Flow Rate: 1 mL/minute

Temperature: 25° C.

Detection wavelength: 227 nm

Injection volume: 50 μL

Retention time: 10.5 minutes

By comparison with a calibration curve generated from known stocksolutions, the amount of drug eluted into the release solution duringany time period of the experiment can be calculated.

Methods and results for measuring release profiles are published in A.Finkelstein et al., “The Conor Medsystems Stent: A programmable DrugDelivery Device,” TCT 2001 Conference, Washington, D.C., September 2001.

While the invention has been described in detail with reference to thepreferred embodiments thereof, it will be apparent to one skilled in theart that various changes and modifications can be made and equivalentsemployed, without departing from the present invention.

1. A method for preparing an implantable medical device, which methodcomprises: a) providing an implantable medical device with a pluralityof holes; b) loading into the plurality of holes an amount of aliquefied therapeutic agent, which amount is sufficient to form atherapeutic agent layer; c) allowing said liquefied therapeutic agentlayer to at least partially solidify; d) loading into the plurality ofholes an amount of a liquefied bioresorbable polymer which amount issufficient to liquefy a portion of the therapeutic agent layer, therebyallowing a portion of the therapeutic agent layer to be disposed withina mixing layer; e) allowing said liquefied bioresorbable polymer andsaid portion of the therapeutic agent layer to solidify; wherein aconcentration of therapeutic agent contained within the mixing layerupon solidification is smaller than a concentration of therapeutic agentcontained in the therapeutic agent layer; wherein the loading of theliquefied therapeutic agent and the liquefied bioresorbable polymer areperformed in a dropwise matter; and further wherein steps d and e mayoptionally be repeated to form multiple mixing layers.
 2. The method forpreparing an implantable medical device of claim 1, wherein theliquefied therapeutic agent is formed by dissolving the therapeuticagent in a solvent.
 3. The method for preparing an implantable medicaldevice of claim 1, wherein the liquefied bioresorbable polymer is formedby dissolving the bioresorbable polymer in a solvent.
 4. The method forpreparing an implantable medical device of claim 1, further comprisingthe step of forming a barrier layer by loading into the plurality ofholes an amount of a liquefied biocompatible polymer, which amount issufficient to form a barrier layer, wherein the barrier layer is locatedadjacent the therapeutic agent layer.
 5. The method for preparing animplantable medical device of claim 4, wherein the liquefiedbiocompatible polymer is liquefied by maintaining the biocompatiblepolymer at a temperature that is higher than its melting point, or glasstransition temperature.
 6. The method for preparing an implantablemedical device of claim 4, wherein the liquefied biocompatible polymeris formed by dissolving the biocompatible polymer in a solvent.
 7. Themethod for preparing an implantable medical device of claim 1, whereinthe liquefied bioresorbable polymer loaded into the holes does notcontain the therapeutic agent.
 8. The method for preparing animplantable medical device of claim 1, wherein the liquefied therapeuticagent layer comprises the therapeutic agent and a pharmaceuticallyacceptable polymer.
 9. The method for preparing an implantable medicaldevice of claim 8, wherein the liquefied therapeutic agent layercomprises from about 50% to about 95% therapeutic agent and from about5% to about 50% pharmaceutically acceptable polymer.
 10. The method forpreparing an implantable medical device of claim 1, wherein the loadingof the liquefied therapeutic agent and the liquefied bioresorbablepolymer are performed by a piezoelectric micro-jetting device.
 11. Amethod for preparing an implantable medical device, which methodcomprises: a) providing an implantable medical device with a pluralityof holes; b) loading into the plurality of holes an amount of aliquefied therapeutic agent, which amount is sufficient to form atherapeutic agent layer; c) allowing said liquefied therapeutic agentlayer to at least partially solidify; d) loading into the plurality ofholes an amount of a liquefied bioresorbable polymer which amount issufficient to liquefy a portion of the therapeutic agent layer, therebyallowing a portion of the therapeutic agent layer to be disposed withina mixing layer; e) allowing said liquefied bioresorbable polymer andsaid portion of the therapeutic agent layer to solidify; wherein aconcentration of therapeutic agent contained within the mixing layerupon solidification is smaller than a concentration of therapeutic agentcontained in the therapeutic agent layer; further wherein steps d and emay optionally be repeated to form multiple mixing layers; and whereinthe liquefied therapeutic agent is liquefied by maintaining thetherapeutic agent at a temperature that is higher than its meltingpoint, or glass transition temperature.
 12. A method for preparing animplantable medical device, which method comprises: a) providing animplantable medical device with a plurality of holes; b) loading intothe plurality of holes an amount of a liquefied therapeutic agent, whichamount is sufficient to form a therapeutic agent layer; c) allowing saidliquefied therapeutic agent layer to at least partially solidify; d)loading into the plurality of holes an amount of a liquefiedbioresorbable polymer which amount is sufficient to liquefy a portion ofthe therapeutic agent layer, thereby allowing a portion of thetherapeutic agent layer to be disposed within a mixing layer; e)allowing said liquefied bioresorbable polymer and said portion of thetherapeutic agent layer to solidify; wherein a concentration oftherapeutic agent contained within the mixing layer upon solidificationis smaller than a concentration of therapeutic agent contained in thetherapeutic agent layer; further wherein steps d and e may optionally berepeated to form multiple mixing layers; and wherein the liquefiedbioresorbable polymer is liquefied by maintaining the bioresorbablepolymer at a temperature that is higher than its melting point, or glasstransition temperature.